S-benzoyloxymethyl-thiamines



United States Patent V 30,222 US. Cl. 260-2565 8 Claims Int. Cl. C07d 51/42; A61k 15/12 ABSTRACT OF THE DISCLOSURE This invention relates to new derivatives of thiol-form thiamine and to a method for their preparation. More particularly, the invention relates to such derivatives which contain a benzoyloxymethyl grouping linked through the sulphur atom of open-form thiamine, these new compounds being represented by the following structural formula:

wherein R represents hydrogen, halogen or a lower alkyl from 1 to 3 carbon atoms. The R substituent may be in any of the available positions of the benzene ring but preferably it is in ortho or para position.

The new compounds are chemically identified as 3- (benzoyloxymethylthio 4[N(2 methyl 4 amino 5- pyrimidinomethyl)N formyl]amino A (3) pentenols, but for the sake of brevity, will be named hereinafter S-benzoyloxymethyl-thiamines. I

This invention also includes acid addition salts of the above defined compounds with non-toxic pharmaceutically acceptable organic or inorganic acids, for example hydrohalic acids, e.g. hydrochloric, hydrobromic or hydriodic acid, sulphuric, phosphoric, acetic, propionic, lactic, oxalic, succinic, maleic, tartaric, citric, benzoic, mandelic, methanesulphonic and salicylic acids.

The S-benzoyloxymethyl-thiamine derivatives of this invention and their salts possess remarkable vitamin B, activity, because they are promptly converted to thiamine in the body. Contrary to the thiamine itself which is little absorbed when orally administered, the compounds of this invention are readily absorbed by oral administration and the absorption is substantially proportional to the dosage. Thus the compounds of the invention permit high vitamin B levels in blood and organs, and therefore, they may be usefully employed as nutritional supplements for foods and animal feedstuifs and for therapeutic purposes, particularly for the treatment of conditions resulting from vitamin B deficiency.

The compounds of this invention can be formulated for administration by oral, parenteral or intraduodenal route together with a non-toxic pharmaceutical carrier.

The compositions may be in dosage unit form containing the active ingredient in an amount from 5 to 250 mg. The administration is advantageously in equal doses one or more times daily to give a daily dosage of from 15 to 1000 mg. and preferably from 30 to 500 mg.

The new S-benzoyloxymethyl-thiamine derivatives of the invention are obtained by reacting a metal salt of thiol-form thiamine with a reagent of the formula:

R wherein R is as defined above and X is halogen, particularly chlorine.

Among the metal salts of thiol-form thiamine are alkali metal salts, e.g. sodium, potassium, lithium or alkali-earth metal salts or the ammonium salt. Generally the reaction is carried out in an anhydrous organic solvent e.g. benzene, toluene, hexane, methanol, ethanol, isopropanol, diethyl ether, dioxane, tetrahydrofurane or mixtures thereof. The reaction is preferably carried out at a temperature between room temperature and 0; generally the reaction is accomplished after a period of from 3 to 30 hours at room temperature.

The S-benzoyloxymethyl-thiamine derivative which separates at the end of the reaction may be isolated and purified following standard procedures, for example by simple filtration of my evaporation of the solvent and suitable recrystallization. If desired, the S-acyloxymethyl derivatives of Formula I areconverted into their nontoxic acid addition salts according to known procedure, for example by reacting the bases with an aqueous or alcoholic solution of the appropriate mineral or organic acid. The hydrochloric acid addition salts are preferred.

The following examples are illustrative of the invention.

EXAMPLE 1 A solution of 3.04 g. of sodium salt of thiol-form thiamine in 30 cc. of anhydrous ethyl alcohol is mixed with stirring at room temperature with 1.70 g. of chloromethyl ester of benzoic acid. Stirring is continued at room temperature for about 3 hours, after which 30 cc. of anhydrous ethyl ether is added. The precipitate so obtained, containing sodium chloride together with the final reaction product, is filtered, then suspended in water and filtered again. The sodium chloride is completely removed from the filter cake by repeated washing with water and the S-benzoyloxymethyl-thiamine is dried under vacuum, washed with anhydrous ethyl ether and crystallized from anhydrous ethyl alcohol. Yield: 2.9 g.; M.P. 194-195 C.

1 g. of this product mixed with an alcoholic solution of hydrochloric acid gives the S-benzoyloxymethyl-thiamine hydrochloride, M.P. 178-l80 C. Similarly the hydrobromic, phosphoric, oxalic and citric acid addition salts of S-benzoyloxymethyl-thiamine are obtained.

EXAMPLE 2 By following the same procedure as in Example 1 and treating the potassium salt of thiol-form thiamine with the chloromethyl ester of the o-toluic acid, the S-o-toluyloxymethyl-thiamine is obtained, M.P. 164-165" C. This product, mixed with an alcoholic solution of hydrochloric acid, gives the S-o-toluyloxymethyl-thiamine hydrochloride, M.P. 179 C. In the same manner the S-p-tolyloxymethyl-thiamine and the S-m-toluyloxymethyl-thiamine are prepared and converted into their hydrochloric acid addition salts.

EXAMPLE 3 A solution of 5 g. of sodium salt of thiol-form thiamine in 50 cc. of anhydrous ethyl alcohol is mixed with stirring at room temperature with 2 g. of chloromethyl ester 3 4 of p-chloro benzoic acid. :By following the procedure deatoms; and non-toxic pharmaceutically acceptable acid scribed in Example 1, the S-p-chlorobenzoyloxymethyladdition salts thereof. thiamine is obtained; M.P. 168-170 C. Similarly, by re- 2. The compound having the following formula:

acting sodium salt of thiol-form thiamine with the chloromethyl ester of p-ethyl-benzoic acid and p-isopropyl- 5 CHa-( NH:

benzoic acid, obtained according to the method of M. /CHZCHZOH Descud (Chem. Centralblatt, 1902, I, 974, ibid., 1902, II, N OHz-N 933), the S-p-ethyl-benzoyloxymethylthiamine and the S- p-isopropyl-benzoyloxymethyl-thiamine, respectively, are

obtained and converted into their hydrobromic acid addi- 1O The hydrochloric acid addition salt of the compound Saltsclaimed in claim 2.

EXAMPLE 4 4. The compound having the followin formula:

Biological tests /N CH NHZ The compounds of th1s lnventlon are readily converted CH3 CHzCHzOH to thiamine by homogenates of animal organs. Table I N shows the percent conversion for two representative l compounds of the invention when incubated with brain, CH0 STCHPOTCO heart, liver, kidney and intestine homogenates of normal rats. The incubation lasted for an hour at 37 C. and pH I 7.4 and S-benzoylthiamine monophosphate was d f 5. The hydrochlorlc acid additlon salt of the compound comparison purposes. claimed 1n clalm 4.

TABLE I Compound Brain Heart Liver Kidney Intestine S-benzoylthlamine monophosphate. 16 22 3O 80 43 S-benzoyloxymethyl-thiamine 86 100 100 100 100 S-0-toluyloxymethyl-thiamine 27 86 96 100 100 From the table it is readily apparent that the thioethers The compound havmg the following formula:

of the invention are converted to thiamine by the homog- /N enates of different organs in an amount larger than the CH3 CHZCHzOH corresponding S-benzoyl ester. N CH N Vitamin B activity was demonstrated in man by administering the products of the invention in a single dose H0 s-oH,-o0 o-Q-cr to healthy human beings. The hematic thiamine was measured in samples of blood drawn before the administration The com ound havin the followin formula. of the compounds and 2, 4, 8 and 24 hours after this 40 P g g administration. NE,

In Table II are reported the average values of thiamine cmcmo determined in every sample and the percent variations N from the starting values.

S-benzoyloxymethyl-thiamine hydrochloride was tested HO 34715-0430 in comparison with thiamine hydrochloride, utilised as standard compound. H3

TABLE II Hours after administration Dose, Compound mg. 0 2 4 8 24 g./100 cc. Percent ug/100 cc. Percent gJlOO cc. Percent fig-I100 cc. Percent ng.ll00 cc. Percent Thiamine hydrochloride 200 5.84 100 6.0 102 6.6 113 3.1 104 5.9 100 S-benzoyloxymethylthiamine hydrochloride..." 100 5. 84 100 15.37 263 13.71 234 11.53 197 7.73 132 From the table above it is readily apparent that the S- The compound having the following formula:

benzoyloxy derivatives of the invention possess a higher CH NH and more prolonged vitamin -B activity than that of thi- 2 CHNHZOH amine hydrochloride administered at a double dose. N CH We claim: 1. A member selected from the group consisting of H0 chemical compounds of the formula: References cited K CH CH OH OH UNITED STATES PATENTS N a 2 3,324,124 6/1967 Murakami et al. 260-2565 CHz-NC=C (EHO CHOC o-Q ALEX MAZEL, Primary Examiner.

R R. I. GALLAGHER, Assistant Examiner. in which R is selected from the group consisting of hy- US. Cl. X.R.

drogen, halogen and lower alkyl of from 1 to 3 carbon 260-476; 424-255 

